Enhancing Atoh1 function in hair cell regeneration

增强 Atoh1 在毛细胞再生中的功能

• 批准号: 10604600
• 负责人: Andrew K Groves
• 金额: $ 68.8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604600
• 关键词: Acute; Affect; Alleles; Animals; Cause of Death; Cells; Chronic; Clinical; Cochlea; Complement; Consensus; Data; Ear; Ectopic Expression; Embryo; Engineering; Environment; Epigenetic Process; Epithelial; Future; GFI1 gene; Genes; Genetic; Genetic Engineering; Genetic Transcription; Hair Cells; Hearing; Human; Injury; Intervention; Labyrinth; Mammals; Minority; Morphology; Mus; Natural regeneration; Neonatal; Organ of Corti; Pathology; Patients; Regenerative capacity; Sensorineural Hearing Loss; Severities; Supporting Cell; System; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Type II Hair Cell; Utricle structure; Vertebrates; age related; clinically relevant; comparative efficacy; deaf; deafening; deafness; experimental study; feasibility testing; guinea pig model; hair cell regeneration; hearing impairment; improved; regeneration potential; regenerative; regenerative approach; response; success; transcription factor; transcriptomics

PROJECT SUMMARY Sensorineural hearing loss is caused by the death of hair cells in the organ of Corti, and once lost, cochlear hair cells in humans and other mammals do not regenerate. In contrast, non-mammalian vertebrates can functionally recover from deafening injury by mobilizing supporting cells to divide and differentiate to replace lost hair cells. Over the last 10 years, the consensus from many studies is that supporting cells in the embryonic and neonatal organ of Corti retain a limited capacity to divide and differentiate into hair cells under certain conditions, but that this ability declines precipitously prior to the onset of hearing. One facet of such an age-dependent decline in regenerative potential is the function of the transcription factor Atoh1. Ectopic expression of Atoh1 in embryonic or neonatal cochlear tissue can transform supporting cells or adjacent non-sensory cells into hair cells - but this ability appears to be severely diminished after the onset of hearing in mice. We have shown that additional hair cell transcription factors, such as Gfi1 and Pou4f3, can enhance the ability of Atoh1 to generate hair cell-like cells in older animals, but it is not clear how closely these resemble bona fide hair cells, whether reprogramming is feasible in ears that have been chronically deafened, and whether additional interventions can improve the modest regeneration we observe. This proposal seeks to evaluate the feasibility of transcription factor reprogramming in the mature, deafened cochlea. We will also apply these cochlear regenerative strategies to the mature utricle, which we and others have shown to have a greater capacity for regeneration than the cochlea, and also a better response to transcription factor reprogramming.

项目概要 感音神经性听力损失是由柯蒂氏器中的毛细胞死亡引起的，一旦丧失，耳蜗 人类和其他哺乳动物的毛细胞不会再生。相比之下，非哺乳动物脊椎动物可以 通过动员支持细胞进行分裂和分化以替换，从震耳欲聋的损伤中功能恢复 失去毛细胞。过去 10 年来，许多研究一致认为，支持细胞 胚胎和新生儿的 Corti 器官在以下条件下保留有限的分裂和分化为毛细胞的能力 某些条件下，但这种能力在听力开始之前急剧下降。 这种与年龄相关的再生潜力下降的一个方面是转录因子的功能 阿托1. Atoh1在胚胎或新生儿耳蜗组织中的异位表达可以转化支持细胞或 相邻的非感觉细胞转变为毛细胞 - 但这种能力似乎在出现后严重减弱 老鼠的听力。我们已经证明，额外的毛细胞转录因子，例如 Gfi1 和 Pou4f3，可以 增强 Atoh1 在老年动物中生成毛细胞样细胞的能力，但尚不清楚这些细胞的密切程度如何 类似于真正的毛细胞，对于长期耳聋的耳朵来说，重新编程是否可行， 以及额外的干预措施是否可以改善我们观察到的适度再生。该提案旨在 评估转录因子重编程在成熟、耳聋的耳蜗中的可行性。我们也会 将这些耳蜗再生策略应用于成熟的椭圆囊，我们和其他人已经证明，成熟的椭圆囊具有 比耳蜗具有更强的再生能力，并且对转录因子有更好的反应 重新编程。